Project summary. Insulin resistance plays a major role in the etiology of chronic metabolic diseases, many of which differ with race/ethnicity. Previous studies using mainly indirect methods suggest that insulin sensitivity is lower in African-Americans (AA) vs. European-Americans (EA). However, results are discrepant, differing with the method used and the obesity status of the participants. Our preliminary data using the reference standard glucose clamp indicate that in lean individuals, insulin sensitivity i lower among AA, while in obese individuals, insulin sensitivity is higher among AA. We hypothesize that this race/body mass index (BMI) interaction may be explained in part by significantly lower visceral/hepatic adiposity in AA that results in less impairment of insulin sensitivity among obese AA individuals. Conversely, we hypothesize that inherently greater oxidative stress impairs insulin sensitivity in AA, explaining lower insulin sensitivity in lean AA vs. EA. This is based on our preliminary data indicating that a circulating marker of cumulative oxidative stress was significantly associated with insulin-stimulated glucose disposal in AA but not EA, and that production of reactive oxygen species (ROS) in vitro was greater in AA vs. EA. We propose to test these hypotheses by prospectively comparing skeletal muscle and hepatic insulin sensitivity in healthy lean, overweight, and obese AA and EA using the hyperinsulinemic isoglycemic glucose clamp with tracer-labeled glucose. Analysis of ancestral genetic admixture will permit simultaneous assessment of the contribution of ancestry to main outcomes. With our first aim, we will test the hypothesis that a significant race-by-BMI interaction will be detected n skeletal muscle and hepatic insulin sensitivity, such that at low BMI AA are less insulin sensitive but at high BMI AA are more insulin sensitive, when compared with EA. The second aim will test the hypothesis that at high BMI, AA will have greater hepatic and skeletal muscle insulin sensitivity due to lower hepatic and visceral fat. The third aim will test the hypothesis that greater bioenergetic efficiency and ROS production within skeletal muscle mitochondria will be associated with lower skeletal muscle insulin sensitivity in lean AA. A secondary aim will test the hypothesis that skeletal muscle and hepatic insulin sensitivity are better associated with adipokines, cytokines, lipids, blood pressure, and vascular function in EA than in AA. Relevance. Results from this study elucidating why the underlying pathophysiology of insulin resistance differs with genetic background may guide development of personalized treatment strategies with implications for several chronic metabolic diseases (e.g., type 2 diabetes, cardiovascular disease, and cancer).